Papers of the Month
Extramural
By Megan Avakian and Julie Leibach
Air pollution may trigger DNA modifications tied to Alzheimer’s disease
Fine particulate matter (PM2.5), a type of air pollutant, may contribute to Alzheimer’s disease risk by affecting DNA methylation patterns tied to neuroinflammation, according to NIEHS-funded research. Neuroinflammation, which is an immune response in the central nervous system, is a hallmark of Alzheimer’s disease.
Growing evidence indicates that PM2.5 is a risk factor for Alzheimer’s disease, but the underlying mechanisms are unclear. Results from human and animal studies suggest that changes in DNA methylation, which regulate gene expression, are associated with indicators of Alzheimer’s disease and PM2.5 exposure.
The researchers assessed DNA methylation in human postmortem brain tissues obtained from 159 donors who participated in the Emory Goizueta Alzheimer’s Disease Research Center brain bank program. They also estimated donors’ residential traffic-related PM2.5 exposure at one, three, and five years before death. Using a combination of analytical approaches, the team looked for differences in methylation patterns that could explain links between PM2.5 exposure and Alzheimer’s disease.
Differences at two methylation sites — cg25433380 and cg10495669 — were consistently associated with PM2.5 across all exposure timeframes. One of those sites, cg10495669, is connected to a gene that regulates inflammation. The team also identified 22 methylation sites that may underpin ties between PM2.5 exposure and indicators of Alzheimer’s disease. Several of those sites are located in genes responsible for neuroinflammation and related cell death. In addition, the researchers found links between PM2.5 exposure at the three-year window and methylation changes along a pathway important to life span.
The study is the first to show an association between PM2.5 exposure and varying methylation patterns in the human brain. Results should be verified with a larger sample size across more diverse stages of Alzheimer’s disease, according to the authors. (JL)
Citation: Li Z, Liang D, Ebelt S, Gearing M, Kobor MS, Konwar C, Maclsaac JL, Dever K, Wingo AP, Levey AI, Lah JJ, Wingo TS, Hüls A. 2024. Differential DNA methylation in the brain as potential mediator of the association between traffic-related PM2.5 and neuropathology markers of Alzheimer's disease. Alzheimers Dement; doi: 10.1002/alz.13650 [Online ahead of print 12 Feb. 2024].
Heavy metal exposure linked to earlier menopause
Exposure to heavy metals may be linked to earlier menopause in middle-aged women, NIEHS-researchers reported. The study is the first to assess how metals affect levels of anti-Müllerian hormone (AMH) over time in women approaching menopause.
AMH is a marker of ovarian reserve, or the number of eggs remaining in the ovaries. Ovarian reserve and AMH levels naturally drop in the years leading up to menopause, called the menopausal transition period. A woman reaches menopause once she has gone 12 months without a menstrual period.
The team analyzed data from about 550 middle-aged women enrolled in the Study of Women's Health Across the Nation, a racially and ethnically diverse investigation of how the menopausal transition affects health. The researchers assessed the relationship between levels of arsenic, cadmium, mercury, and lead in urine and levels of AMH in blood in the 10 years leading up to the women’s last menstrual period.
Higher urinary concentrations of arsenic and mercury were associated with lower AMH at the final menstrual period. The top one-third of arsenic and mercury exposures were associated with 32% and 40% lower AMH levels, respectively, compared to the bottom one-third of exposures. During the menopausal transition period, women in the top one-third of cadmium and mercury exposures experienced faster rates of AMH decline — 9% and 7%, respectively — than women in the bottom one-third.
According to the authors, these results indicate that certain heavy metals may act as ovarian toxicants by depleting ovarian reserve in women approaching menopause. (MA)
Citation: Ding N, Wang X, Harlow SD, Randolph JF Jr, Gold EB, Park SK. 2024. Heavy metals and trajectories of anti-Müllerian hormone during the menopausal transition. J Clin Endocrinol Metab dgad756.
Phthalate exposures associated with high numbers of preterm birth
Nearly 57,000 cases of preterm birth a year may be attributable to phthalate exposures, according to a study funded by NIEHS and others. Associated economic and medical care costs are an estimated $3.8 billion, highlighting a need for robust exposure prevention efforts.
The consequences of preterm birth include infant and childhood mortality; adverse psychological, behavioral, and educational outcomes in young adulthood; and cardiovascular disease and diabetes in later life. Phthalates — synthetic chemicals widely used in consumer products, such as vinyl flooring and personal -care items — have been implicated in preterm birth. However, little is understood about the potential effects of newer phthalates, such as diisononyl phthalate (DiNP) and diisodecyl phthalate (DiDP), used to replace di-2-ethylhexyl phthalate (DEHP) in food packaging.
Using data from the NIH Environmental influences on Child Health Outcomes (ECHO) Program for 1998-2022, the researchers studied associations between 20 phthalates and gestational age at birth, birthweight, and birth length for 5,006 mother-child pairs. They also investigated negative birth outcomes and financial costs that could be attributable to phthalate exposure.
Although DEHP exposure was associated with preterm birth, the replacement chemicals DiDP, DiNP, and di-n-octyl phthalate showed stronger associations. The team also estimated that 56,595 cases of preterm birth in 2018 could be attributed to phthalate exposures. For that year, lost economic productivity and additional medical care costs due to phthalate-induced preterm birth could have ranged from $1.6 to $8.1 billion.
The results suggest substantial opportunities for phthalate exposure prevention, according to the authors. They added their findings also show that DEHP replacements are not safer, indicating a need to regulate chemicals with similar properties as a class. (JL)
Citation: Trasande L, Nelson ME, Alshawabkeh A, Barrett ES, Buckley JP, Dabelea D, Dunlop AL, Herbstman JB, Meeker JD, Naidu M, Newschaffer C, Padula AM, Romano ME, Ruden DM, Sathyanarayana S, Schantz SL, Starling AP, Hamra GB; programme collaborators for Environmental influences on Child Health Outcomes. 2024. Prenatal phthalate exposure and adverse birth outcomes in the USA: a prospective analysis of births and estimates of attributable burden and costs. Lancet Planet Health 8(2):e74–e85.
Moderate radon exposure associated with increased risk of stroke in women
Exposure to moderate levels of radon was associated with increased risk of stroke in middle-aged and older women, NIEHS-funded researchers reported. The findings add to limited research on how exposure to the radioactive gas affects stroke risk in women, who are more prone to strokes than men.
Rocks and soil naturally release radon, which can accumulate inside buildings by entering through small cracks. Although radon is a leading cause of lung cancer and is implicated in stroke, radon testing and mitigation tend to be less common than recommended in the U.S.
The researchers used data from nearly 160,000 women ages 50-79 when they joined the Women’s Health Initiative, a decades-long study of postmenopausal women in the U.S. They estimated exposure by linking each woman’s home address to federal data on radon levels, which they grouped into low-, middle-, and high-radon exposures. Using medical records and death certificates, they confirmed stroke outcomes in participants during the approximately 13-year follow-up.
Stroke risk was 6% and 14% greater among women living in middle and high exposure areas, respectively, compared to those with the lowest radon exposures. Notably, stroke risk was significantly elevated among women exposed to radon at mid-levels, which are below the recommended threshold for taking mitigation steps, according to the U.S. Environmental Protection Agency.
Overall, the results suggest a relationship between radon exposure and increased risk of stroke among women. According to the authors, confirmation of this trend in a more diverse population could extend the generalizability of these findings and help inform stricter radon action levels to protect public health. (MA)
Citation: Buchheit SF, Collins JM, Anthony KM, Love SM, Stewart JD, Gondalia R, Huang DY, Manson JE, Reiner AP, Schwartz GG, Vitolins MZ, Schumann RR, Smith RL, Whitsel EA. 2024. Radon exposure and incident stroke risk in the Women’s Health Initiative. Neurology 102(4).
(Megan Avakian and Julie Leibach are senior science writers at MDB, Inc., a contractor for the NIEHS Division of Extramural Research and Training.)
